Triclosan (TCS) is a common antibacterial agent used in personal care products and many consumer products. The public is exposed to TCS as a result of its prevalence in a multitude of daily care products, waterways, and environmental samples. This is evidenced by the fact that TCS has been detected in human plasma, breast milk, and body fluids, and a large U.S. population (74.6%) had detectable TCS levels in their urine. Although it is structurally similar to other highly-regulated environmental chemicals, TCS is poorly regulated and is generally accepted as safe. Studies have increasingly linked TCS to a range of health and environmental effects; however, there are no mechanism-based studies with relevant animal models that directly link TCS exposure to negative health effects in humans. Following long-term TCS exposure, mice exhibited compensatory hepatocyte proliferation and fibrogenesis, which are accompanied by oxidative stress. Using the procarcinogen diethylnitrosamine to initiate tumorigenesis in mice, we further demonstrated that TCS, as a potent liver tumor promoter, accelerates hepatocellular carcinoma (HCC) development. TCS-treated mice exhibited a large increase in tumor multiplicity, size, and incidence compared to control mice. Increased ALT levels, histological alterations, and profound inflammatory responses following TCS treatment suggest that TCS is responsible for liver injury that leads to disrupted liver integrity and function. Another prominent feature of the TCS-treated livers is significant induction of Toll-like receptors (TLRs) 2 and 4, key molecules in the innate immunity system. Acting as sensors for pathogens, TLRs as a first-line defense against invading microorganisms detect conserved microbial components. Intestinal bacterial components are known to cause liver diseases; an emerging body of evidence also indicates that both TLR2 and TLR4 are closely linked with gut microbiota-driven liver tumorigenesis. Thus, we hypothesize that by disrupting the homeostasis of gut flora that release bacterial components into the portal vein, antibacterial TCS activates the TLR signaling through which the liver chronically deteriorates by undergoing fibrosis, inflammation, and subsequent tumorigenesis. We will examine the biochemical and cellular events as well as the composition of enteric microflora that link TLRs to TCS-induced liver pathogenesis in mice that are Tlr2-/Tlr4-heterozygous or null mice (Aim 1). The progression of HCC growth induced by TCS is still largely unknown. Since TCS-treated mice exhibited fatty liver disease (NAFLD)-like features, we therefore propose examining the effect of TCS on NAFLD progression to steatosis and to HCC by using an animal model in which high-fat diet alone in genetically modified mice can lead to the development of HCC. The hypothesis is that these mice will develop liver cancer more rapidly in animals with TCS, pointing to a synergy in tumor formation between obesity-related changes in lipogenesis and TCS-mediated hepatocellular damage and fibrosis (Aim 2). The findings originating from these studies will provide a novel opportunity to illustrate the human health complications that TCS may elicit.